Opioids are analgesic agents which exhibit opium or morphine-like properties. Both acute and chronic opioid administration can produce tolerance, as indicated by a lowered responsiveness to the administration of this drug. Drug tolerance necessitates higher doses, which can be associated with side effects that often limit long-term use. Mao, J., et al., Chronic Morphine Induces Down Regulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity, J. Neuroscience, 2002, 22(18):8312-8323; Sjogren, P., et al., Hyperalgesia And Myoclonus In Terminal Cancer Patients Treated With Continuous Intravenous Morphine, Pain, 1993, 55:93-97; Ossipov, M. H., et al., The Loss of Antinociceptive Efficacy of Spinal Morphine In Rats With Nerve Ligation Injury Is Prevented By Reducing Spinal Afferent Drive, Neurosci Lett., 1995, 199:87-90; Foley, K. M., et al., Opioids and Chronic Neuropathic Pain, NEJM, 2003, 348:1279-1281.
Tolerance to the analgesic effects of narcotics remains a major impediment to the use of these drugs in the treatment of pain Also, pain due to nerve compression or nerve invasion is a prominent component of cancer pain, and is resistant to treatment with currently available narcotic and non-narcotic analgesics.
Current methods of treating opioid tolerance often involve the NMDA receptor and inhibiting it. NMDA antagonists, however, have been found to be highly toxic and are only able to partially reverse morphine tolerance at best and cannot reverse established tolerance. The high toxicity limits the clinical use of antagonists. Hence, a need exists for compositions and methods for: (1) the effective inhibition of the development of opioid tolerance; (2) reversal or reduction of opioid tolerance; (3) reducing opioid dependence; (4) effective inhibition of physical dependence; and (5) reducing or inhibition of addiction.